Vehicle for topical delivery of anti-inflammatory compounds

ABSTRACT

A vehicle for topical delivery which contains a liquid eutectic mixture of hydrophobic compounds.

FIELD OF THE INVENTION

The present invention relates to the preparation of semisolidformulations for topical delivery of pharmaceutically activeingredients, designed for pain control and inflammation treatment.

BACKGROUND OF THE INVENTION

Topical pharmaceutical preparations of different types have been usedfor treatment of rheumatic and arthritic pain for decades. Semisolidcompositions comprise plant derivatives, such as capsaicin (red hotpepper stinging substance) or turpentine (pine tar component) ointments,homeopathic extract and liniments (Opodeldoc Rus), mustard plasters,menthol rubs, essential oil balms and many others were used for a longtime, mainly as local irritants. Such irritation improves local bloodflow, accelerates injured tissue recovery, and switches attention fromchronic pain from inflammation.

By including non-steroid anti-inflammatory drugs (NSAID) into ointmentor cream application onto the desired location allows for effectivecontrol of muscle and joint pain intensity. Moreover, when NSAID isapplied topically, local drug concentration in muscle and joint tissuesis significantly higher than in non-treated sites. Additionally, thereis no intensive metabolism in liver (so called “first-pass effect”)because such drugs do not pass through the liver before action.

The required amount of NSAID is lower than an oral dose to achievesimilar anti-inflammative and analgesic effects. The most common sideeffect of NSAID is serious irritation of stomach and gastro-intestinalmucosa. This is substantially diminished with local topicalapplications.

Topical NSAID formulations are very popular in Europe, Asia and Far Eastregions. Examples of compositions include Voltaren Emulgel® (Voltarol™in UK), a 1.16% Diclofenac diethylammonium emulsion cream with isopropylalcohol, Feldene® Gel (0.5% Piroxicam water-ethyl alcohol gel),Ibuprofen and Ketoprofen gels of different strengths (5-10%), and 1-10%lndomethacin in alcohol. DMSO-containing creams and many otherformulations are widespread in many countries as OTC remedies for musclepain, sport minor injuries, rheumatic and back pain treatment, etc.

Generally, topical NSAID preparations do not have attributableside-effects such as gastric irritation and internal bleeding.Advantageously, the compounds provide relatively fast action onset andmoderate efficacy in treatment of local muscle and joint pain. The mainproblems of these products is low drug loading due to low solubility inthe cream components. High loading can be reached by use of concentratedalcohols, i.e. ethyl alcohol, isopropyl alcohol with polyethylene glycoland propylene glycol suitable as solvents for NSAIDs. Drug loading ishigh and can easily reach 5-10% or greater, e.g., 5% Ibuprofen gel withisopropyl alcohol, 1% Indomethacin gel based on ethyl alcohol or even10% Indomethacin ointment with dimethylsulfoxide.

These solvents are widely used for gel preparation, but widespread useis often limited due to the proclivity for skin irritation. A furtherlimitation is realized in fast termination of action for gelpreparations since the drug precipitates from solution subsequent towater absorption from the body tissue. Further, solvents in highconcentration often irritate the skin due to drying and delipidisationand may initiate contact dermatitis and allergy. Drug, insoluble inwater media and body fluids, precipitates in the upper skin layers anddoes not penetrate inside, seriously limiting anti-inflammatory action.Similar behavior was observed for polyethylene glycol (mixture ofPEG4000 and PEG400) hydrophilic topical base.

Traditional hydrophobic vehicles such as fixed oils, mineral oil,petrolatum, lanolin and wax based ointments, along with emulsion creams(either O/W or W/O type) are less irritating to human skin, but thesepresent another complication—solubility. Drug loading in such vehiclesis limited by the solubility of the drug in the lipid phase. Forexample, the solubility of Indomethacin in olive or corn oil is below0.2%, whereas Ketoprofen is about 1.5% and Piroxicam below 0.05%.According to Benita et al. “Submicron Emulsions as Colloidal DrugCarriers for Intravenous Administration: Comprehensive PhysicochemicalCharacterization”, J. Pharm Sci., 1993, November 1982 (11), pp. 1069-79,even for low drug loading, stability of the dispersed system isquestionable. A 0.1% Indomethacin submicron emulsion lost stabilityafter 1 month storage.

Use of more polar hydrophobic compounds may help to improve solubilityof NSAIDs. Tocopherol acetate, triethyl citrate, glycerin monolaurate,glycerin monooleate (Myverol™ 18-9) dissolve between 1.5 and 2 timesmore Indomethacin or Diclofenac (in acidic form). Nevertheless, thisloading is insufficient to obtain an effective NSAID emulsion.Transdermal adhesive systems such as skin patches and plasters withIndomethacin or Diclofenac present low efficacy by the same reasoning.

A further method to increase drug solubility in the oil phase is to usehighly polar compounds, miscible with named phase. Solvents such asEthoxyethylene glycol (Transcutol™), dimethylisosorbide (DMIS),Isopropylideneglycerin (Solketal™), ethoxylated furanyl alcohol(Glucofurol™) visibly boost drug implementing in the separatehydrophobic phase. However, upon mixing with water, most of the solventis extracted into the water and the dissolved drug precipitatesimmediately and almost entirely from the oil phase.

Recently developed submicron emulsions (SME) employed as a base forNSAIDs, provides very effective delivery and exert pronouncedimprovement for drug action in Friedman et al. (U.S. Pat. No.6,113,921). However, low solubility of NSAIDs in a lipid phase of suchemulsions leads to shortened periods of efficacy and drug precipitationfrom the oil phase during storage. High loading, desirable for optimalactivity of topical NSAID preparation for SME is achievable only forhighly lipophilic compounds, such as Naproxen, Ketoprofen or Ibuprofenwith significantly lower anti-inflammatory activity.

Eutectic mixture use in topical applications is rather limited. Anexample is EMLA cream, developed by Astra-Zeneca. The liquid, formed bymixing two crystalline bases of local anesthetics, Lidocain andPrilocain due to eutectic formation serves as an oil phase in the creamfor topical application. The cream, containing 5% of such oil phase,provides excellent stability and anesthetic action.

In view of the limitation in the anti-inflammatory drug art, thereexists a need for an improved composition which overcomes theshortcomings presently encountered.

SUMMARY OF THE INVENTION

It has been found that a eutectic mixture of camphor, menthol, thymoland similar compounds is a powerful solvent for non-steroidalanti-inflammatory drugs and other substances. The solubility ofIndomethacin, Diclofenac, or Ketoprofen in the mixture increased between3 and 20 fold. As a particular advantage, the eutectic mixture was foundto be safe, non-toxic and present synergistic behavior inanti-inflammatory action of NSAIDs due to anti-inflammatory propertiesof camphor and skin penetration enhancing properties of menthol.

The eutectic mixture can be combined with pharmaceutically acceptableoils and lipids and included into topical formulations. The compositionswere found to allow much higher drug loading than existing ointmentbases and creams, showed no skin irritation and provided enhanceddelivery properties for incorporated drugs.

Prior to enhancing on a discussion of the preparation, some generalproperties of the menthol and camphor will be established.

The menthol used was (1R, 2S, 5R)-5-methyl-2-(1-methyethyl)-cyclohexanolwith a molecular weight of 156.27 and melting point of 42° C. Mentholgenerally has a peppermint odor. It is well known as a skin irritant andpenetration enhancer in Tsuk (U.S. Pat. No.4,933,184). It is widely usedin many topical formulations for relief of arthritic and rheumatic pain.Natural L-menthol exerts a cooling or refreshing sensation due to directinteraction with cold sensitive receptors in the skin. This wasestablished in the Handbook of Pharmaceutical Excipients, Third Edition,ed. A. H. Kibbe, Pharmaceutical Press, London, U.K., 2000, pp. 334-335.Menthol has been used as mild local anesthetic and as volatile aromaticcomponent for breath relief in obstruction and cold treatment in Hugheset al. (U.S. Pat. No. 5,322,689).

Similar properties are known for camphor1,7,7-trimethylbicyclo[2,2,1]heptanone-2, having a molecular weight of152.24. Camphor has a high melting point (180° C.) and is a veryvolatile substance with strong pine-like odor that sublimes even at roomtemperature and pressure. Initially, camphor found use as a stimulant,but now camphor is mainly used as a component in topical preparations.It is often used in nasal decongestants and aromatic compositions.

Either menthol or camphor separately or in combination are widely usedin topical formulations, mainly due to their irritant action, receptorinteraction and specific traditional odor, frequently associated withtime-honored remedies. Ben Gay™ ointment, Tiger™ balm, Menthol Chest Ruband similar compositions are well known and popular.

Certain external analgesic products containing between 10% to 60% methylsalicylate, more than 3% to 11% camphor and 1.25% to 16% menthol, eithersingly or in combination, cause irritation or mild inflammation of theskin for the purpose of relieving pain in muscles, joints, or visceradistal to the site of application by stimulating depressing cutaneoussensory receptors in Ivy et al. (U.S. Pat. No. 5,013,726).

Topical preparations for joint relief include that provided for in Langet al. (U.S. Pat. No. 4,731,200) for an aqueous-alcohol compositioncontaining benzylidene-camphor derivatives, Ivy et al. (U.S. Pat. No.5,013,726) for a lotion containing methyl salicylate, camphor andmenthol, Ivy et al. (U.S. Pat. No. 5,124,320) for an analgesic lotioncontaining menthol and camphor, Heywang et al. (U.S. Pat. No. 5,144,081)for a pharmaceutical composition containing camphor and Singh (U.S. Pat.No. 5,175,152) for a composition with methyl salicylate, menthol andcamphor.

These substances have been advertised for use in relieving joint pain,such as the elbow, knee, thumb area, ankle, neck, wrist, hand andfinger, shoulder, etc.

To improve solubility of non-steroidal anti-inflammatory drugs, acomplex mixture of surfactants, polyglycol(s) and glycerides has beenused in combination with polymers and sodium or potassium hydroxidesolutions as established in Morton et al. (U.S. Pat. No. 5,376,688).

In Kaplun-Fischoff et al. “Testosterone Skin Permeation Enhancement byMenthol Through Formation of Eutectic with Drug and Interaction withSkin Lipids”, J. Pharm Sci. 1997, December, 1986 (12) pp.1394-9, theresearchers observed that menthol forms a eutectic mixture withcrystalline testosterone. The formed mixture is not liquid, but thecomposition demonstrated a significant improvement in transdermalpenetration of testosterone. According Kaplun-Frischoff et al., mentholaffects skin permeation by a dual mechanism: by forming a eutectic withthe penetrating compound, thereby increasing its solubility in skinceramides and by altering the barrier properties of the stratum corneum.

A careful investigation of existing compositions containing menthol andcamphor in different ratios showed that there is no one example ofspecific use of menthol and camphor in combination as eutectic mixturein order to improve solubility of an included drug. Allanti-inflammatory components used in such formulations are liquid(methylsalycilate, benzylnicotinate, etc.) and easily miscible with oilcomponents of the creams or ointments. There is no limitation forsolubility, and these topicals can contain up to 60% of activecomponent, e.g., methylsalycilate), Altadonna (U.S. Pat. No. 5,853,768).

In the documentation there has not been a recognition of amenthol-to-camphor ratio in the eutectic region. In all cases, theexisting preperations are used only due to their mild irritative oranti-inflammatory activity (camphor, nicotinic acid derivatives) or skinpenetration enhancement properties of menthol itself.

It has now been recognized that a radical increase of drug solubility ina eutectic mixture of polar hydrophobic compounds allows preparation ofeffective and safe topical formulations with these drugs for externalapplication.

Having thus described the invention, reference will now be made to theaccompanying drawings illustrating preferred embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of anti-inflammatory solubility ina mixture of MCT and a menthol/camphor mixture;

FIG. 2 is a graphical representation of Indomethacin solubility inoleaginous vehicles and in a menthol/camphor vehicle;

FIG. 3 is a graphical representation of Piroxicam solubility inoleaginous vehicles and in a eutectic vehicle; and

FIG. 4 is a graphical representation of drug content change duringstorage.

Similar numerals in the figures denote similar elements.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A mixture of equimolar amounts of crystalline camphor and menthol atroom temperature immediately led to liquified crystals. This mixture wasused in the preparations as an effective solvent for some NSAIDcompounds.

FIG. 1 graphically represents the solubility of Diclofenac (as freeacid) in mixtures of medium chain triglycerides (MCT, standard oilvehicle, Labrafac® TGCC) with different levels of added menthol-camphoreutectic mixture. Diclofenac saturation concentration at 25° C. wasevaluated by HPLC. Solubility in a pure equimolar menthol-camphoreutectic mixture was found to be 11.8 times higher than in pure MCT.

Similar behavior was observed also for Indomethacin, illustratedgraphically in FIG. 2, maximum solubility in equimolar eutecticmenthol-camphor mixture is 160 mg/ml, compared with 2 mg/ml in the soyoil or 4.8 mg/ml in MCT oil. For comparison, Ho et. al. “PenetrationEnhancement by Menthol Combined with a Solubilization Effect in a MixedSolvent System”, J. Controlled Release, Feb. 12, 1998 ; 51 (2-3), pp.301-11, investigated influence of menthol addition (up to 12% by weight)as solubility enhancer for Indomethacin in different pharmaceuticalvehicles such as water, ethanol, propylene glycol and theircombinations. In any case maximal solubility hardly reached 2%(approximately 20 mg/ml).

In FIG. 3, further graphic data are presented for Piroxicam.

Piroxicam solubility is significantly lower than aromatic NSAIDs,however, use of the eutectic menthol-camphor mixture increased drugsolubility at room temperature between 8 and 11 times, from 0.35 mg/mlin MCT to 2.9-3.2 mg/ml in pure eutectic mixture and to 1.8 mg/ml in MCTwith 60% menthol-camphor (1:1) content.

If alpha-tocopherol or tocopherol acetate is used as the oil phase,solubility can reach 30-35 mg/ml for tocopherol-menthol-camphorcomposition 5:3:3 (parts by weight).

Use of other ratios for menthol-camphor eutectic mixture (e.g., 2:1 or1:2; 3:4 or 4:3) also improves solubility for most of investigatedsubstances but in slightly lower extent. Very significant improvement insolubility was achieved with replacement of menthol for another eutecticforming substance, thymol (2-isopropyl-5-methylphenol, thyme oilcomponent).

Obtained solutions of NSAIDs in lipid phase containing menthol-camphoror another eutectic mixture vehicle are stable in wide temperature rangeand non-irritating for human and animal skin (Dreize' test). Based onthese observations different topical formulations with NSAIDs wereprepared and will now be discussed in the examples.

EXAMPLE 1 Indomethacin 1% Cream

Per 250 g CREAM INGREDIENTS % cream Indomethacin USP 1.00 2.5 MediumChain Triglycerides (Labrafac ® CCTG) 4.00 10 Soy Lecithin(Phospholipon ® S-80) 1.00 2.5 (±) Camphor USP 3.00 7.5 L-(−)-MentholUSP 3.00 7.5 Tween ™-80 (Polysorbate 80, USP) 1.60 4.0 TPGS (Tocopherolpolyethylene glycol 0.80 2.0 1000 succinate) Sodium Ethylenediaminetetraacetate 0.10 0.25 (EDTA sodium) Carbopol ® 971P 1.50 3.75 GlycerinUSP 2.50 6.25 Water 81.50 203.75Vehicle (Eutectic Mixture) Preparation:

(±) Camphor and L-Menthol were mixed together during heating at between40 and 50° C. until a clear liquid was obtained.

Oil Phase Preparation:

Soy lecithin, MCT oil and TPGS were mixed together at 45° C. until ahomogenous solution was obtained. Tween™-80 as then added, followed bythe addition of the eutectic mixture vehicle. The mixture was stirreduntil completely dissolved. Indomethacin (USP grade) was added to thewarm mixture and stirred for 10 minutes at 45° C. until completelydissolved.

Water Phase Preparation:

EDTA disodium salt, glycerin and Tween™-80 were added to water (90% ofcalculated amount) and stirred until completely dissolved.

Emulsification:

The solution was combined with the oil phase, mixed thoroughly usingappropriate mixer and homogenized using high pressure homogenizer(Avestin® C-5) at 8,000-12,000 psi, (600-800 bar). The mixture waspassed through the homogenizer between 2 and 3 times.

Cream Preparation:

In a separate vessel Carbopol® 971P was mixed with 10% of calculatedamount of water and soaked for between 2 and 6 hours. Carbopol® pastewas combined with the homogenized emulsion using a high shearrotor-stator type mixer (Omni GLH mixer) at 18,000-24,000 rpm.Triethanolamine was added gradually while mixing until the desired pHand viscosity were achieved.

EXAMPLE 2 Indomethacin 2% Cream

The composition was prepared in accordance with the methodology ofExample 1. Per 100 g Per CREAM INGREDIENTS cream 1000 g Lipid PhaseIndomethacin USP 2.00 20.00 Medium Chain Triglycerides (Labrafac ® CCTG)8.00 80.00 Egg Lecithin S-75 2.00 20.00 (±) Camphor USP 6.00 60.00L-(−)-Menthol USP 6.00 60.00 Tween ™-80 (Polysorbate-80 USP) 2.00 20.00TPGS (Tocopherol polyethylene glycol 0.80 8.00 1000 succinate) WaterPhase Sodium Ethylenediamine tetraacetate 0.10 1.00 (EDTA sodium)Bronopol ® (2-Brom-2-nitro-1,3-propanediol) 0.10 1.00 Triethanolamine0.50 5.00 Ultrez ™ 10 0.50 5.00 Glycerin 2.20 22.00 Water 69.80 698.00

Bronopol® (2-Brom-2-nitro-1,3-propanediol) was added to the water phaseas an antibacterial preservative. Ultrez™ was used as a viscosityregulating component instead of Carbopol® without the preliminaryhydration step as set forth in Example 1.

EXAMPLE 3 Diclofenac Sodium 1% Cream

The composition of the emulsion for 1% Diclofenac cream presented inTable 3. The cream contains approximately 14% of the oil phase with aratio MCT: Camphor: Menthol of 6:3:4. CREAM INGREDIENTS Per 100 g creamMedium Chain Triglycerides (Labrafac ® CCTG) 6.00 (±) Camphor USP 3.00L-(−)-Menthol USP 4.00 Tocopherol succinate 0.02 Soy Lecithin(Phospholipon ® S-80) 0.12 Tween ™-80 (Polysorbate - 80) 2.00 DiclofenacSodium USP 1.00 Water 80.38 Hydrochloric acid 1N 3.5

The oil phase was prepared by dissolving MCT, oil Tocopherol succinate,lecithin, camphor, and menthol at 45° C.

The water phase was prepared by dissolving Diclofenac sodium andTween™-80 in hot 85° C. purified water.

After mixing the warm oil and hot water phases, hydrochloric acid wasadded to coarse emulsion while intensive stirring. The pH was adjustedto between 3.5 and 4.2. Homogenization was conducted as described inExample 2. After a fine emulsion was obtained, it was filtered through0.45 micron PTFE membrane filter. The emulsion was used for creampreparation by addition of Carbopol® 971 as a gelling agent to a finalconcentration of 1.5% with pH adjustment to between 4.5 and 5.0.

1.5% Diclofenac sodium emulsion (high loading) was prepared by a similarmanner. The composition is identical to that tabulated in Table 3.Balance was adjusted with water and hydrochloric acid.

EXAMPLE 4 Ibuprofen 5% Cream

5% Ibuprofen cream was prepared as described in Example 2. Thecomposition of the emulsion for 5% Diclofenac cream is presented inTable 4. The cream contains approximately 26% of the oil phase with aratio MCT: Camphor: Menthol of approximately 10 4.25:1:1. Per 100 g PerCREAM INGREDIENTS cream 300 g Ibuprofen 5.00 15.00 Medium ChainTriglycerides (Labrafac ® CCTG) 13.75 41.25 Soy Lecithin (Phospholipon ®S-80) 1.20 3.60 (±) Camphor USP 3.25 9.75 L-(−)-Menthol USP 3.25 9.75Tween ™-80 (Polysorbate-80, USP) 2.00 6.00 TPGS (Tocopherol polyethyleneglycol 0.80 2.40 1000 succinate) Sodium Ethylenediamine tetraacetate0.10 0.30 (EDTA sodium) Bronopol ™ 0.10 0.30 Triethanolamine 1.00 3.00Carbopol ® 934P 1.00 3.00 Glycerin 2.20 6.60 Water 66.35 398.10

EXAMPLE 5 Piroxicam 0.5% Cream

The composition was prepared by the method described in Example 4, butL-(−)-menthol was replaced with thymol (2-isopropyl-5-methylphenol). Thecream contained approximately 28% of the oil phase with a ratioMCT:Camphor:Thymol:Tocopherol acetate of approximately 2:5:5:2. Per 100g Per CREAM INGREDIENTS cream 250 g Piroxicam 2.00 5.00 Medium ChainTriglycerides (Labrafac ® CCTG) 3.00 7.50 Soy Lecithin (Phospholipon ®S-80) 2.00 5.00 (±) Camphor USP 7.50 18.75 Thymol 7.50 18.75 Tween ™-80(Polysorbate-80, USP) 2.50 6.25 Tocopherol acetate (Vitamine E acetate)2.00 5.00 EDTA 0.10 0.25 Carbopol ® 934P 1.50 3.75 Glycerin 2.20 5.50Triethanolamine 0.90 2.25 Water 69.70 174.25

EXAMPLE 6 Reference

Emulsion with Indomethacin, prepared according to U.S. Pat. No.6,113,921. Per 100 g cream 0.5% Indo 1.0% Indo (low (high CREAMINGREDIENTS loading) loading) Indomethacin 0.5 1.0 Medium ChainTriglycerides (MCT oil) 17.0 17.0 Egg Lecithin (Phospholipon ® E-80) 0.80.8 Emulphor EL-620 (polyethoxylated castor oil) 1.6 1.6 Carbopol ® 9401.7 1.7 Glycerin 2.2 2.2 EDTA sodium salt 0.05 0.05 Tocopherol acidsuccinate 0.04 0.05 Triethanolamine 0.65 0.65 Water 75.3 74.5

Indomethacin (0.5 g for low loading and 1.0 g for high loadingemulsions) was dissolved in a preheated (60° C.) mixture of egglecithin, tocopherol succinate and MCT oil. This mixture was emulsifiedwith a water phase (water with Emulfor EL-620, EDTA sodium and glycerin)using a high shear mixer for 5 minutes at 20,000 rpm to form anemulsion.

Further treatment of the emulsion was conducted in a high pressurehomogenizer at 800 bar (12,000 psi) for 6 cycles. Thereafter, theemulsion was cooled to room temperature, and pH was adjusted to between5.6 and 6.5. Part of emulsion was gelled using Carbopol® 940 to form acream; another part was stored at room temperature in tightly closedamber glass containers for 6 months to observe the physical stability.

Diclofenac sodium (1.0% and 1.5% drug loading) emulsions were preparedin a similar manner to Example 6.

To estimate drug precipitation, the stored emulsion samples either forthe reference Example 6, low and high loaded or invention related(Examples 1 and 2) were filtered through PTFE membrane filters. TheIndomethacin content in the filtrates was measured using the HPLCmethod. FIG. 4 illustrates the results.

Low loaded emulsion, prepared in accordance with U.S. Pat. No.6,113,921, showed reasonable stability during storage, but with anincrease in the initial Indomethacin loading, the final concentration ofnon-precipitated drug decreases drastically. In contrast, the eutecticmixture vehicle emulsion, prepared in accordance with the presentinvention, maintains drug content.

Similar results have been obtained for Diclofenac sodium emulsions. In acomposition containing 1% of the drug, stability for both formulationswas observed. In a composition containing 1.5% Diclofenac sodiumemulsion in the menthol-camphor eutectic mixture, stability was observedfor at least 3 months at room temperature, while identically loadedreference emulsion demonstrated significant drug precipitation duringthe same period.

Anti Inflammatory Activity “In Vivo”:

Investigations on animals (rats, carrageenan induced paw edema model)showed significant anti-inflammatory action of the topically appliedcompositions containing the eutectic vehicle.

AUC ratio for edema volume (calculated by trapezoidal rule for t=0-6hours). Indomethacin cream Indomethacin gel Control (example 2) - 2 mgof (Sumitomo Pharm.) (non-treated) Indomethacin/rat 2 mg ofIndomethacin/rat 100% 32% (±12%) 114% (±39%)

Although embodiments of the invention have been described above, it isnot limited thereto and it will be apparent to those skilled in the artthat numerous modifications form part of the present invention insofaras they do not depart from the spirit, nature and scope of the claimedand described invention.

1-20. (canceled)
 21. A method for solubilizing a non-steroidalanti-inflammatory drug comprising: combining the non-steroidalanti-inflammatory drug with a liquid eutectic mixture of at least twocompounds selected from the group consisting of camphor, menthol andthymol.
 22. The method according to claim 21 wherein the solvent vehiclecomprises a eutectic mixture comprising camphor and menthol.
 23. Themethod according to claim 22 wherein the camphor and menthol are presentin a ratio of 4:1 to 1:4.
 24. The method according to claim 23 whereinthe camphor and menthol are present in a ratio of 2:1 to 1:2.
 25. Themethod of claim 21 wherein said camphor is selected from the groupconsisting of D-isomer, L-isomer, racemic camphor or a mixture ofcamphor isomers.
 26. The method of claim 21 wherein said menthol isselected from the group consisting of D-isomer, L-isomer, racemicmenthol or a mixture of menthol isomers.
 27. The method according toclaim 21 wherein the solvent vehicle further comprises a liquidhydrophobic component.
 28. The method according to claim 27 wherein theliquid hydrophobic component is selected from the group consisting ofpharmaceutically acceptable glycerin ester, aliphatic esters, aromaticesters, waxes, lipids, fats, lipid soluble vitamins, hydrocarbons,silicone polymers, tocopherols, or mixture thereof.
 29. The methodaccording to claim 28 wherein said liquid hydrophobic component istocopherol.
 30. The method according to claim 29, wherein the tocopherolis alpha-tocopherol or tocopherol acetate.
 31. The method of claim 21,wherein the non-steroidal anti-inflammatory drug is selected from thegroup consisting of: indomethacin, diclofenac, ketorolac, piroxicam,tenoxicam, ketoprofen, flurbiprofen, ibuprofen, Naproxen, meloxicam andsalicylic acid
 32. The method according to claim 31 wherein thenon-steroidal anti-inflammatory drug is selected from the groupconsisting of: diclofenac, piroxicam, indomethacin, ketoprofen,meloxicam, and ibuprofen.
 33. The method according to claim 32 whereinthe non-steroidal anti-inflammatory drug is diclofenac.
 34. The methodaccording to claim 32 wherein the non-steroidal anti-inflammatory drugis piroxicam.
 35. The method according to claim 32 wherein thenon-steroidal anti-inflammatory drug is indomethacin.
 36. The methodaccording to claim 32 wherein the non-steroidal anti-inflammatory drugis ibuprofen.
 37. The method of claim 21 further comprising a polaracetylated di or mono-glyceride and/or, a hydrobobic ester.
 38. Themethod of claim 27, wherein the composition further comprises a polartriglyceride.
 39. The method of claim 28, wherein the polar triglycerideis selected from the group consisting of medium chain triglyceride andacetylated monoglyceride.
 40. A drug composition comprising: anon-steroidal anti-inflammatory drug in solution in a liquid eutecticmixture of at least two compounds selected from the group consisting of:camphor, menthol and thymol.
 41. The composition of claim 40 wherein theliquid eutectic mixture comprises camphor and menthol.
 42. Thecomposition of claim 41, wherein the camphor and menthol arc present inthe eutectic mixture in a ratio from 4:1 to 1:4.
 43. The composition ofclaim 41, wherein the ratio of said camphor and menthol are present insaid eutectic mixture in a ratio from 2:1 and 1:2.
 44. The compositionof claim 40 wherein the non-steroidal anti-inflammatory drug is selectedfrom the group consisting of diclofenac, piroxicam, indomethacin,ketoprofen, meloxicam and ibuprofen.
 45. The composition of claim 44wherein the drug is diclofenac.
 46. The composition of claim 44 whereinthe drug is piroxicam.
 47. The composition of claim 44 wherein the drugis indomethacin.
 48. The composition of claim 44 wherein the drug isibuprofen.
 49. The composition of claim 40 wherein said camphor isselected from the group consisting of D-isomer, L-isomer, racemiccamphor or a mixture of camphor isomers.
 50. The composition of claim 40wherein said menthol is selected from the group consisting of D-isomer,L-isomer, racemic menthol or a mixture of menthol isomers.
 51. Thecomposition of claim 40 further comprising a liquid hydrophobiccomponent.
 52. The composition of claim 51 wherein the hydrophobiccomponent is tocopherol.
 53. The composition of claim 52, wherein thetocopherol is alpha-tocopherol or tocopherol acetate.
 54. Thecomposition of claim 40 further comprising a glyceride and/or, ahydrophobic ester.
 55. The composition of claim 54, wherein thecomposition further comprises an acetylated glyceride.
 56. Thecomposition of claim 55, wherein the acetylated glyceride is selectedfrom the group consisting of diglycerides and acetylated monoglycerides.57. The composition of claim 40, wherein said solvent vehicle is evenlydistributed in water containing media forming an homogeneous mixture.58. The composition of claim 57 further comprising viscosity modifiers,surfactants, preservatives, fragrances and other excipients to promotestable formulation, suitable for topical application to the skin.